Mammalian cells cultured in vitro will be used to evaluate fundamental and practical aspects of the treatment of cancer with densely ionizing radiations, hypoxic cell radiosensitizers and cytotoxic agents used in chemotherapy. Well tried radiobiological systems will be used to compare the oxygen enhancement ratio (OER) and the relative biological effectiveness (RBE) for the various neutron beams used for radiotherapy in the United States and Europe. Radiobiological studies will be performed with the heavy ion beams at the BEVALAC and with the negative pi meson beam at Los Alamos. A study will be made of the interaction of high and low LET radiations using the X-ray and charged particle facilities at the Radiological Research Accelerator Facility at Brookhaven National Laboratory. A number of nitroimidazoles and other classes of compounds such as dihydroquinolines will be tested and compared as radiosensitizers and cytotoxic agents specific for hypoxic cells. Particular emphasis will be placed on the combination of misonidazole and anti-oxidants such as MTDO. Preliminary data indicate that the radiosensitizing properties of misonidazole and MTDQ are additive, while the antioxidant completely inhibits the cytotoxic properties of the nitroimidazole. This observation will be studied in detail with hypoxic cells in culture and extended to animal studies. The question will be addressed of a link between hypoxic cell cytotoxicity observed in culture and the neurological symptoms noted in vivo with laboratory animals and humans. The potential carcinogenicity of hypoxic cell sensitizers will be assessed by the in vitro transformation assay system, and the basic mechanism of action of this class of compounds investigated. A number of chemotherapeutic agents will be investigated to determine the extent to which hypoxia confers protection on mammalian cells in culture, and the variation between drugs of their age-response function.